De novo MYH9 mutation in congenital scalp hemangioma

Abstract

Congenital hemangiomas are tumor-like vascular malformations with poorly understood pathogenesis. We report the case of a neonate with a massive congenital scalp hemangioma that required urgent neurosurgical removal on the second day of life because of concern for high-flow arteriovenous shunting. Exome sequencing identified a rare damaging de novo germline mutation in MYH9 (c.5308C>T, p.[Arg1770Cys]), encoding the MYH9 nonmuscle myosin IIA. MYH9 has a probability of loss-of-function intolerance (pLI) score of >0.99 and is highly intolerant to missense variation (z score = 5.59). The p.(Arg1770Cys) mutation substitutes an evolutionarily conserved amino acid in the protein's critical myosin tail domain and is predicted to be highly deleterious by SIFT, PolyPhen-2, MetaSVM, and CADD. MYH9 is a known regulator of cytokinesis, VEGF-regulated angiogenesis, and p53-dependent tumorigenesis. These findings reveal a novel association of germline de novo MYH9 mutation with congenital hemangioma.

Keywords: hemangioma.

Figure 1.

Preoperative MRI/MRA imaging and tissue histology of a patient with a large congenital scalp hemangioma. (A,B) MR imaging of the brain with and without gadolinium, demonstrating a large extracranial contrast enhancing lesion in the left temporal area; axial and coronal T1-weighted post-gadolinium MR images shown; (C–E) axial, coronal, and sagittal reconstructions of the 3T time-of-flight MR angiogram images, demonstrating the arterial supply of patient's congenital scalp hemangioma arising from superior temporal and occipital arteries; (F,G) 20× images of H&E stains of congenital hemangioma showing dense fibrous stroma with large irregular vessels.

Figure 2.

Identification of MYH9 de novo damaging missense germline mutation in a patient harboring large congenital scalp hemangioma. (A) Pedigree structure and the Sanger chromatograms demonstrating the MYH9 c.5308C>T, p.[Arg1770Cys] mutation. The black circle represents the affected patient (K12-1); the unfilled square and circle represent patient's father (K12-3) and mother (K12-2), respectively, who do not have this phenotype. (B) Schematic representation of MYH9 protein structure and previously reported mutations affecting MYH9. Note the diversity of syndromes associated with the MYH9 mutations. Arrows depict the approximate location of previously described amino acid substitutions resulting from mutations in the MYH9. Each protein modification is color-coded and correlates with a key of all MYH9-associated syndromes. Dark rectangles represent functional domains. p.[Arg1770Cys] is depicted below the schematic; the amino acid sequence alignment for 12 different species is represented below, demonstrating phylogenetic conservation of Arg1770.